Summary Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Group 3 MB, the most aggressive MB subtype, is more frequently associated with gene amplification and/or protein overexpression of the MYC oncogene, thus commonly referred to as MYC-driven MB. The molecular mechanisms underlying MYC hyper-activation in MB are still unclear, as only a small portion of MYC-driven MBs is caused by MYC genomic amplification. This knowledge gap hinders the development of MYC-targeted MB therapies. Here, we focus on developing a novel MB therapy based on targeting the transcription co-activator TAZ, an essential MYC upstream activator. Our preliminary studies show for the first time that TAZ is an essential and druggable MYC activator in MB cells. TAZ is highly expressed in MYC-amplified human MB cells and their xenografts. TAZ silencing downregulates MYC and inhibits MB cell growth in vitro. Enforced TAZ expression induces MYC expression in MB cells. We further show that the FDA-approved drug Verteporfin (VP) inhibits TAZ-TEAD complex formation, suppresses MYC expression and inhibits MB cell tumor propagation. Our preliminary results support a comprehensive study of the TAZ-MYC signaling axis and its oncogenic role in driving MB initiation and growth. For clinical translation, it is necessary to determine the efficacy of VP treatment in pre- clinical MB models, and further define VP's molecular drug action, likely involving direct VP-TAZ interaction and the inhibition of TAZ-MYC signaling axis. This project will be built on our working hypothesis that the TAZ- TEAD transcription complex activates MYC expression in MB cells through transactivating MYC enhancers, and TAZ targeting effectively inhibits MYC expression and MYC-driven MB. Aim 1 will determine if TAZ promotes MB cell tumorigenicity through transcriptional activation of MYC. Aim 2 will determine if the FDA- approved drug VP inhibits MYC-driven MB in vivo, and further determine if VP acts through targeting the TAZ- MYC signaling axis. Our goals are to uncover a novel TAZ-MYC signaling axis that promotes MYC expression and MB cell tumorigenicity, and to further establish a clinically translatable strategy for TAZ-targeted MB therapy based on repurposing the FDA-approved drug VP. The success of this project will significantly advance our knowledge of MYC hyper-activation and MB tumorigenesis, which knowledge may be widely applicable to various MYC-driven human cancers. Determining the therapeutic efficacy of VP in pre-clinical MB models will lay a solid foundation for repurposing VP for treating high-risk MYC-driven MB, and will also provide novel molecular insights to facilitate the development of potent VP derivatives for TAZ targeting.